Sepsis is a systemic inflammatory response to infection or trauma associated with and mediated by the activation of a number of host defense mechanisms including the cytokine network, leukocytes, and the complement and coagulation/fibrinolysis systems. Sepsis may be caused by bacterial, fungal, viral and other infections as well as by non-infective stimuli such as multiple trauma, severe burns, and organ transplantation. Within hours or days sepsis can progress to spontaneous clotting in the blood vessels, severe hypotension, multiple organ failure, and death.
Despite the clinical use of modern antibiotics, there remains a significant level of mortality due to ineffective treatment of patients with sepsis. Patients who are immunocompromised due to e.g. prophylaxis against graft rejection are also at increased risk. More leukemia patients die from sepsis than from their leukemia. It is estimated that there are 500 000 episodes of sepsis per year in the USA with a 35% crude mortality rate and 200 000 episodes of septic shock with a 40-70% mortality rate. Sepsis is the leading cause of death in non-coronary intensive care units. 40% of hospital deaths after injury are due to multiple organ dysfunction syndrome caused by sepsis.
Several attempts have been made in recent times to find an effective new therapy for sepsis patients. Considerable effort has been made to produce monoclonal antibodies against key mediators of inflammation, e.g. anti-tumour necrosis factor monoclonal antibodies, but these have proved clinically ineffective and have also been found to have dangerous side effects in sepsis patients. Another approach has been to use purified human coagulation factors, such as activated protein C (APC) including recombinant human APC (e.g. Xigris®). However, these APC based sepsis therapies have had little clinical impact. There are a number of reasons for this which include the anti-coagulant activity of APC which leads to an increased risk of haemorrhage thus the drug is excluded for sepsis which develops in patients post surgery or post trauma. For the same reason APC based sepsis therapeutics are excluded for leukemia patients who are at high risk of bleeding. Sepsis can progress rapidly and the relatively slow mode of action of APC based sepsis therapeutics is a disadvantage relative to the rapid progression of acute sepsis. Xigris was withdrawn from sale on Oct. 25, 2011.
Histones are small basic proteins that function in the cell nucleus to regulate gene expression and complex with DNA to form nucleosomes which assemble into chromatin structure. Xu et al, (Nat. Med. 2009. 15:1318-21) have reported a cytotoxic activity for histones released in response to inflammatory processes with the extracellular histones acting as mediators of endothelial cell dysfunction, organ failure and death in sepsis.
The present invention is predicated on the finding that polyanions can complex with extracellular histones in the circulation of a living animal and inhibit their cytotoxic activity. In addition the polyanions can complex with extracellular histones and prevent histone accumulation in organs. Further, these polyanions may have insignificant anticoagulant properties.